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Biallelic PMS2 Mutations in a Family with Uncommon Clinical and Molecular Features

We describe a patient with constitutional mismatch repair-deficiency (CMMR-D) in whom the syndrome started at age 10 with the development of multiple adenomas in the large bowel. In the successive 25 years, four malignancies developed in different organs (rectum, ileum, duodenum, and lymphoid tissue...

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Autores principales: Pedroni, Monica, Ponz de Leon, Maurizio, Reggiani Bonetti, Luca, Rossi, Giuseppina, Viel, Alessandra, Urso, Emanuele Damiano Luca, Roncucci, Luca
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9690098/
https://www.ncbi.nlm.nih.gov/pubmed/36360190
http://dx.doi.org/10.3390/genes13111953
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author Pedroni, Monica
Ponz de Leon, Maurizio
Reggiani Bonetti, Luca
Rossi, Giuseppina
Viel, Alessandra
Urso, Emanuele Damiano Luca
Roncucci, Luca
author_facet Pedroni, Monica
Ponz de Leon, Maurizio
Reggiani Bonetti, Luca
Rossi, Giuseppina
Viel, Alessandra
Urso, Emanuele Damiano Luca
Roncucci, Luca
author_sort Pedroni, Monica
collection PubMed
description We describe a patient with constitutional mismatch repair-deficiency (CMMR-D) in whom the syndrome started at age 10 with the development of multiple adenomas in the large bowel. In the successive 25 years, four malignancies developed in different organs (rectum, ileum, duodenum, and lymphoid tissue). The patient had biallelic constitutional pathogenic variants in the PMS2 gene. We speculate that besides the PMS2 genotype, alterations of other genes might have contributed to the development of the complex phenotype. In the nuclear family, both parents carried different PMS2 germline mutations. They appeared in good clinical condition and did not develop polyps or cancer. The index case had a brother who died at age three of lymphoblastic leukemia, and a sister who was affected by sarcoidosis. Tumor tissue showed diffuse DNA microsatellite instability. A complete absence of immunoreactivity was observed for the PMS2 protein both in the tumors and normal tissues. Next-generation sequencing and multiple ligation-dependent probe amplification analyses revealed biallelic PMS2 germline pathogenic variants in the proband (genotype c.[137G>T];[(2174+1_2175-1)_(*160_?)del]), and one of the two variants was present in both parents—c.137G>T in the father and c.(2174+1-2175-1)_(*160_?)del in the mother—as well as c.137G>T in the sister. Moreover, Class 3 variants of MSH2 (c.1787A>G), APC (c.1589T>C), and CHEK2 (c.331G>T) genes were also detected in the proband. In conclusion, the recognition of CMMR-D may sometimes be difficult; however, the possible role of constitutional alterations of other genes in the development of the full-blown phenotype should be investigated in more detail.
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spelling pubmed-96900982022-11-25 Biallelic PMS2 Mutations in a Family with Uncommon Clinical and Molecular Features Pedroni, Monica Ponz de Leon, Maurizio Reggiani Bonetti, Luca Rossi, Giuseppina Viel, Alessandra Urso, Emanuele Damiano Luca Roncucci, Luca Genes (Basel) Case Report We describe a patient with constitutional mismatch repair-deficiency (CMMR-D) in whom the syndrome started at age 10 with the development of multiple adenomas in the large bowel. In the successive 25 years, four malignancies developed in different organs (rectum, ileum, duodenum, and lymphoid tissue). The patient had biallelic constitutional pathogenic variants in the PMS2 gene. We speculate that besides the PMS2 genotype, alterations of other genes might have contributed to the development of the complex phenotype. In the nuclear family, both parents carried different PMS2 germline mutations. They appeared in good clinical condition and did not develop polyps or cancer. The index case had a brother who died at age three of lymphoblastic leukemia, and a sister who was affected by sarcoidosis. Tumor tissue showed diffuse DNA microsatellite instability. A complete absence of immunoreactivity was observed for the PMS2 protein both in the tumors and normal tissues. Next-generation sequencing and multiple ligation-dependent probe amplification analyses revealed biallelic PMS2 germline pathogenic variants in the proband (genotype c.[137G>T];[(2174+1_2175-1)_(*160_?)del]), and one of the two variants was present in both parents—c.137G>T in the father and c.(2174+1-2175-1)_(*160_?)del in the mother—as well as c.137G>T in the sister. Moreover, Class 3 variants of MSH2 (c.1787A>G), APC (c.1589T>C), and CHEK2 (c.331G>T) genes were also detected in the proband. In conclusion, the recognition of CMMR-D may sometimes be difficult; however, the possible role of constitutional alterations of other genes in the development of the full-blown phenotype should be investigated in more detail. MDPI 2022-10-26 /pmc/articles/PMC9690098/ /pubmed/36360190 http://dx.doi.org/10.3390/genes13111953 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Case Report
Pedroni, Monica
Ponz de Leon, Maurizio
Reggiani Bonetti, Luca
Rossi, Giuseppina
Viel, Alessandra
Urso, Emanuele Damiano Luca
Roncucci, Luca
Biallelic PMS2 Mutations in a Family with Uncommon Clinical and Molecular Features
title Biallelic PMS2 Mutations in a Family with Uncommon Clinical and Molecular Features
title_full Biallelic PMS2 Mutations in a Family with Uncommon Clinical and Molecular Features
title_fullStr Biallelic PMS2 Mutations in a Family with Uncommon Clinical and Molecular Features
title_full_unstemmed Biallelic PMS2 Mutations in a Family with Uncommon Clinical and Molecular Features
title_short Biallelic PMS2 Mutations in a Family with Uncommon Clinical and Molecular Features
title_sort biallelic pms2 mutations in a family with uncommon clinical and molecular features
topic Case Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9690098/
https://www.ncbi.nlm.nih.gov/pubmed/36360190
http://dx.doi.org/10.3390/genes13111953
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